Fused bicyclic and tricyclic pyrimidine compounds as tyrosine kinase inhibitors

Abstract

Fused bicyclic or tricyclic compounds of formula (I): wherein A, B, C, X, Y, m, and n are defined herein. Also disclosed are a method for inhibiting EGFR kinase activity and a method for treating cancer with these compounds.

What is claimed is: 
     
       1. A compound of formula (I): 
       
         
           
           
               
               
           
         
         Wherein the compound is a furo[2,3-d]pyrimidine compound
 X is N; 
 Y is O, S, or NR 2 , in which R 2  is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; 
 A is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halo, cyano, nitro, OR 3 , OC(O)R 3 , C(O)R 3 , C(O)OR 3 , C(O)NR 3 R 4 , NR 3 R 4 , NHC(O)R 3 , NHC(O)NR 3 R 4 , NHC(S)R 3 , NHC(O)OR 3 , SO 2 R 3 , SO 3 R 3 , or SO 2 NR 3 R 4 , in which each of R 3  and R 4 , independently, is H, alkyl, alkenyl, alkynyl, silyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, R 3  and R 4  are optionally substituted, or R 3  and R 4 , together with the nitrogen atoms to which they are bonded, are heterocycloalkyl, heterocycloalkenyl, or heteroaryl; 
 B is aryl or heteroaryl; 
 each of m and n, independently, is 0, 1, or 2; and 
 ring C is 
 
       
       
         
           
           
               
               
           
         
         
            or 
         
       
       
         
           
           
               
               
           
         
         
            in which 
           R″, is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halo, nitro, cyano, OR a , C(O)OR a , C(O)NR a R b , NR b C(O)R a , NHC(O)NR a R b , NR b C(S)R a , NHSO 2 R a , or NR a R b , in which each of R a  and R b , independently, is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, R a  and R b  are optionally substituted, or R a  and R b , together with the nitrogen atoms to which they are bonded, are heterocycloalkyl, heterocycloalkenyl, or heteroaryl, 
           R′ is NR b C(O)R a′ , R a′  being 
         
       
       
         
           
           
               
               
           
         
         
            in which R 6  is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, C(O)R c , C(O)OR c , C(O)NR c R d , or CH 2 NR c R d , in which each of R c  and R d , independently, is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, or R c  and R d , together with the nitrogen atoms to which they are bonded, are heterocycloalkyl, heterocycloalkenyl, or heteroaryl, and R 7  is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; 
           Z is O, and W is CR 5 , in which R 5  is alkenyl, alkynyl, aryl substituted with OR a , or NR b C(O)R a , heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halo, nitro, C(O)OR a , C(O)NR a R b , NR b C(O)R a , NHC(O)NR a R b , NR b C(S)R a , NHSO 2 R a , or NR a R b . 
         
       
     
     
       2. The compound of  claim 1 , wherein the compound is of formula (II): 
       
         
           
           
               
               
           
         
       
     
     
       3. The compound of  claim 1 , wherein B is phenyl and n is 0. 
     
     
       4. The compound of  claim 3 , wherein m is 1 and A is OR 3 , R 3  being H, aryl, heteroaryl, or C 1-3  alkyl optionally substituted with aryl or heteroaryl. 
     
     
       5. The compound of  claim 4 , wherein X is N, Y is NH, and Z is O. 
     
     
       6. The compound of  claim 2 , wherein B is phenyl and n is 0. 
     
     
       7. The compound of  claim 6 , wherein A is C(O)OR 3  and m is 0. 
     
     
       8. The compound of  claim 7 , wherein X is N, Y is NH, and Z is O. 
     
     
       9. The compound of  claim 8 , wherein W is CR 5 , in which R 5  is halo. 
     
     
       10. The compound of  claim 6 , wherein and R″ is OR a . 
     
     
       11. The compound of  claim 10 , wherein m is 1 and A is OR 3 , R 3  being H, aryl, heteroaryl, or C 1-3  alkyl optionally substituted with aryl or heteroaryl. 
     
     
       12. The compound of  claim 11 , wherein X is N, Y is NH, and Z is O. 
     
     
       13. The compound of  claim 2 , wherein the compound is one of the following compounds: 
       
         
           
           
               
               
           
         
       
     
     
       14. A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein the compound is a furo[2,3-d]pyrimidine compound
 X is N; 
 Y is O, S, or NR 2 , in which R 2  is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; 
 A is alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halo, cyano, nitro, OR 3 , OC(O)R 3 , C(O)R 3 , C(O)OR 3 , C(O)NR 3 R 4 , NR 3 R 4 , NHC(O)R 3 , NHC(O)NR 3 R 4 , NHC(S)R 3 , NHC(O)OR 3 , SO 2 R 3 , SO 3 R 3 , or SO 2 NR 3 R 4 , in which each of R 3  and R 4 , independently, is H, alkyl, alkenyl, alkynyl, silyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, R 3  and R 4  are optionally substituted, or R 3  and R 4 , together with the nitrogen atoms to which they are bonded, are heterocycloalkyl, heterocycloalkenyl, or heteroaryl; 
 B is aryl or heteroaryl; 
 each of m and n, independently, is 0, 1, or 2; and 
 ring C is 
 
       
       
         
           
           
               
               
           
         
         
            in which 
           R′ is NR b C(O)R a′ , R a′  being 
         
       
       
         
           
           
               
               
           
         
         
            in which R 6  is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, C(O)R c , C(O)OR c , C(O)NR c R d , or CH 2 NR c R d , in which each of R c  and R d , independently, is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, or R c  and R d , together with the nitrogen atoms to which they are bonded, are heterocycloalkyl, heterocycloalkenyl, or heteroaryl, and R 7  is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, 
           in which R b  is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, 
           Z is O, and W is CR 5 , in which R 5  is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halo, nitro, C(O)OR a , C(O)NR a R b , NR b C(O)R a , NHC(O)NR a R b , NR b C(S)R a , NHSO 2 R a , or NR a R b , in which each of R a  and R b , independently, is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, R a  and R b  are optionally substituted, or R a  and R b , together with the nitrogen atoms to which they are bonded, are heterocycloalkyl, heterocycloalkenyl, or heteroaryl. 
         
       
     
     
       15. The compound of  claim 14 , wherein the compound is of formula (II): 
       
         
           
           
               
               
           
         
       
     
     
       16. The compound of  claim 15 , wherein m is 1 and A is OR 3 , R 3  being H, aryl, heteroaryl, or C 1-3  alkyl optionally substituted with aryl or heteroaryl. 
     
     
       17. The compound of  claim 15 , wherein the compound is one of the following compounds: 
       
         
           
           
               
               
           
         
       
     
     
       18. A pharmaceutical composition, comprising a compound of  claim 2  and a pharmaceutically acceptable carrier. 
     
     
       19. A pharmaceutical composition, comprising a compound of  claim 15  and a pharmaceutically acceptable carrier.